Robotic versus laparoscopic hepatectomy for liver malignancies (ROC'N'ROLL): a single-centre, randomised, controlled, single-blinded clinical trial

Summary Background Robotic hepatectomy (RH) has been increasingly adopted for the treatment of liver malignancies despite lacking evidence from randomised trials. We aimed to determine the effect of RH compared to laparoscopic hepatectomy (LH) on quality of life in patients undergoing minimally invasive hepatectomy for liver malignancies. Methods This single-blinded, randomised trial was conducted at a tertiary care academic centre (DRKS00027531). Patients with resectable liver malignancies were assessed for eligibility and randomly assigned to either RH or LH with stratification by type of malignancy and difficulty of resection. Patients were blinded to the treatment allocation. The primary outcome was the mean quality of life within 90 days after surgery, measured with the role functioning scale of the European Organisation for Research and Treatment of Cancer QLQ-C30 questionnaire. Secondary outcomes included operating time, morbidity, blood loss, conversion rate, postoperative recovery, and resection margin status. Findings Between February 21, 2022, and Sep 18, 2023, 80 patients (RH: n = 41, LH: n = 39) were included and analysed on an intention-to-treat basis. Role functioning scores did not differ between RH and LH (mean [SD], 74.3 [23.3] versus 79.6 [22.3]; mean difference −5.3, 95% CI −15.6 to 5.1, p = 0.547). The comprehensive complication index was not significantly different between the study groups (8.9 [23.1] versus 15.5 [23.9], p = 0.137). There were no differences in other perioperative outcomes. Interpretation RH yielded similar outcomes in quality of life and can be considered a safe alternative to LH. Funding None.


Scientific Background
Liver surgery remains the only curative treatment for patients with primary or secondary liver malignancies.
2][3][4][5] From patient´s perspective, however, being able to maintain one's usual life after cancer surgery is crucial.Although the assessment of the patient´s ability to fulfill different roles in their daily life (e.g., to be able to return to work, to care for oneself, to participate in social activities) is quite complex, role functioning is a core construct and major focus in health outcome research in oncology. 6,7Patient-reported outcome measures (PROMs) enable the measurement of patients' symptom burden and role functioning after cancer treatment. 8The most widely used validated questionnaire in oncology to assess HRQoL is the EORTC QLQ-C30. 9After surgery, patient´s health-related quality of life (HRQoL) is usually impaired in the first 3 months. 10,11 surgical oncology, strategies to improve HRQoL are urgently needed but high-quality data from prospective studies remain scarce.In recent years, minimally invasive liver surgery (MILS) has been increasingly used for treatment of liver malignancies. 12However, there is currently no randomized controlled trial existing to compare the HRQoL as primary outcome in patients treated by MILS for primary and secondary liver malignancies.One randomized controlled trial comparing laparoscopic liver resections and open liver resections in colorectal liver metastases demonstrated lower postoperative complications and better postoperative HRQoL in patients treated laparoscopically. 5,13However, HRQoL was assessed as secondary outcome with the Short Form 36 questionnaire, which has not been primarily designed and validated for oncological patients.In MILS, robotic-assisted surgery is an emerging specialty which allows surgeons to perform more precise movements with enhanced dexterity and delicate dissection compared to conventional laparoscopic techniques. 14,15The robotic system offers an improved visualization without the need for an additional assistant to hold the camera, a comfortable operating position for the operating surgeon, eliminates unnatural postures, and suppresses tremor associated with conventional laparoscopy.
Complex liver resections, advanced hilar dissections, and curved parenchymal dissections might be more accessible for robotic surgery compared to laparoscopic surgery.Thus, a more precise surgery could result in enhanced recovery of patients and improved HRQoL after liver resection.
Unfortunately, the current evidence comparing laparoscopic versus robotic liver resections is only limited on cohort studies.7][18][19] Taken together, advantages of robotic-assisted surgery might result in a more precise surgery with enhanced recovery of patients and improved HRQoL after liver resection.

Aim of the trial
The Roc'n'Roll trial aims to compare the postoperative HRQoL during 90 days after surgery by the EORTC QLQ-C30 role functioning scale after laparoscopic and robotic-assisted liver resection.Furthermore, surgical characteristics outcomes, pathological outcomes, perioperative morbidity, and costs of both surgical techniques will be evaluated as secondary outcomes.the mean QoL using the RF scale (range: 0-100).The RF will be evaluated before surgery, and at postoperative days 30, 60, and 90.If the patient is willing to respond the survey on follow-up by email or telephone, this will be separately documented.

Type and extent of liver resection
The type of liver resection will be documented as anatomic or non-anatomic liver resection and the extent of resection as major (defined as anatomic resection of >3 liver segments) or minor liver resection, respectively.

Difficulty of liver resection
The difficulty of liver resection will be assessed by the IWATE-criteria with following six difficulty indices before surgery 21 (Appendix B): 1. Tumor location, 2. Extent of liver resection, 3. Tumor size, 4. Proximity to major vessel, 5. Liver function, 6. Hybrid technique.A scoring system 0-12 will be used and scores >6 will be defined as "difficult".

Operating time [min]
Time from skin incision until placement of last skin staple/suture.

Total blood loss [ml]
Intraoperative blood loss will be measured according to the blood collected in the suction containers.
Spilling water and ascites will be subtracted.Furthermore, swabs will be squeezed, and their content will also be sucked and added to the fluid collected in the suction containers.

Conversion rate to open surgery
The conversion rate to open liver resection will be documented.

Time-to-functional recovery [days]
The postoperative functional recovery is achieved if the following four criteria are fulfilled: 1) Pain control with oral medication (numeric rating scale <4); 2) Solid food intake e) Time to independent mobility or level of preoperative level [days]: Preoperative level of the mobility scale 22 or a positive score for 8 of 10 items (see Appendix E).

Postoperative hospital stay [days]
Time from the day of operation until the day of discharge.

Postoperative intermediate/intensive care unit stay [days]
Days on the intermediate care unit (IMU or intensive care unit (ICU) after surgery.Patient´s stay in the recovery room exceeding 24 hours is counted as ICU stay.

Readmission to intermediate/intensive care unit stay
Postoperative readmission to the intermediate/intensive care unit until POD 90

Readmission rate
Unplanned readmission at hospital within 90 days after surgery

Need for invasive interventions
Invasive interventions such as placement of interventional drains, endoscopic retrograde cholangiopancreaticography (ERCP) with stent placement, chest tube placement, invasive ventilation, and re-laparotomy will be documented up to 90 days after surgery.

Postoperative medical complications
The following set of predefined complications will be considered as postoperative non-surgical clincal events and documented in the Roc'n'Roll-Trial in line with the definitions of the common terminology criteria for adverse events version 5.0 if not otherwise specified: Postoperative delirium 26 Acute kidney insufficiency 27 .

Postoperative surgical complications
The following set of predefined complications will be considered as postoperative surgical clinical events and documented in the Roc'n'Roll-Trial in line with the definitions of the common terminology criteria for adverse events version 5.0 if not otherwise specified:

Perioperative morbidity
Perioperative morbidity and mortality will be documented according to the Clavien-Dindo-Classification until 90 days after surgery 29 .

Pathological characteristics
Pathological characteristics including tumor size, nodal status, margin status, and lymphvascular invasion will be documented as provided by the pathological report.

Days in home environment 30 days and 90 days of surgery 30 [days]
Days in home environment is calculated from the date of surgery using hospitalization and mortality data.
Death of a patient in hospital or after discharge within 30 days (or 90 days) will be assigned as "0".A discharge in a postdischarge nursing facility will not be counted as days at home.

Discharge destination from hospital
Discharge destination will be classified as home, nursing home, acute-care hospital, and rehabilitation facility.

Oncologic intended therapy
The return to intended oncologic therapy following surgery will be recorded at postoperative day 90.

HRQoL
The QLQ-C30 20 and the EQ-5D-5L questionnaire will be used to assess the HRQoL (see Appendix A and C).All questionnaires will be evaluated before surgery, and at postoperative days 30, 60, and 90.If the patient is willing to respond the survey on follow-up by email or telephone, this will be separately documented.

Costs
Economic evaluation will be performed as cost-utility analyses using quality-adjusted life years (QALY) as endpoint with a time horizon of 90 days. 31The use of hospital healthcare resources will be collected from the case report forms and clinical information system.The following resources will be assessed: duration of admission on general ward and intensive/intermediate care unit, surgical approach, radiological and endoscopic procedures, outpatient clinic visits, emergency room visits, and readmissions.The unit costs of Version 1.0 November 8, 2021 page 13 of 38 laparoscopic and robotic-assisted liver resections will be calculated from costs of operating theatre use, personnel, purchase of disposable materials, and overhead costs.QALYs wil be assessed using the EQ-5D data and the German tariff. 32The incremental cost-utility ratio will be calculated as the difference in mean costs per patient divided by the difference in mean QALYs per patient.

TRIAL DESIGN
This is a prospective randomized controlled, open superiority trial with two parallel study groups.The trial is designed to show that the average HRQoL during 90 days after surgery by the EORTC QLQ-C30 "RF" scale is higher in patients with robotic-assisted liver surgery compared to patients with laparoscopic liver surgery.
The following hypothesis will be tested: H0: No difference between the study groups in the mean of the primary variable "role functioning" H1: "Role functioning" is different between the study groups.
Patients scheduled for curative-intent minimally invasive (robotic-assisted or laparoscopic) liver surgery for confirmed or suspected primary or secondary malignancies will be screened for inclusion into the trial.
Patients meeting the above-mentioned eligibility criteria will be enrolled into the study.Written informed consent is obtained at least on the day before surgery.

Standardization of surgical techniques
Only surgeons with experience of >50 robotic or laparoscopic hepatectomies per year and >25 robotic hepatectomies will be allowed to perform operations in this trial.A CO2 pneumoperitoneum of 12mmHg is established in each group after placing the trocars.Initially, the abdomen is explored for extrahepatic disease.Intraoperative ultrasound of the liver is carried out routinely to exclude previously undetected lesions and to determine the resection planes.A tape is placed around the hepatoduodenal ligament for subsequent intermittent Pringle maneuver during parenchymal transection.
In all groups parenchymal transection is carried out under the following settings: -CO2 pneumoperitoneum of 15-18 mmHg; -Reversed Trendelenburg position; -Positive end-expiratory pressure (PEEP) of 0 mmHg; -Intermittent Pringle maneuver (10 minutes of ischemia followed by 5 minutes of reperfusion).
Parenchymal transection is carried out using the crush-clamp technique in combination with an energy device (LigaSure, Covidien MedTronic or Thunderbeat, Olympus) or bipolar forceps.Vascular and biliary structures with a diameter of >2 mm are divided using titan (Braun) or Hem-o-Lock (VECK) clips.Major pedicles and hepatic veins are divided using Autosuture Endo Gia TM Universal Stapler and Endo Gia TM Universal Angulating 45 mm loading units with 2.5 mm staples (Covidien).
• Laparoscopic group: Four trocars are used (1x 12 mm, 1x 10 mm, 2x 5 mm) in a standardized fashion.Parenchymal transection is carried out using the settings as described above.
• Robotic-assisted group: Five trocars are used (1x 12 mm, 4x robotic trocars) in a standardized fashion.Parenchymal transection is carried out using the settings as described above.

TRIAL INTERVENTIONS
Patient´s perioperative care will be standardized and kept identical except for the approach of surgery, i.e. laparoscopic versus robotic-assisted liver surgery.

Control Group (Group A)
Patients randomized to the laparoscopic group will undergo laparoscopic liver resection.

Experimental Group (Group B)
Patients randomized to the experimental group will undergo robotic-assisted liver resection.

SELECTION OF SUBJECTS
Subjects matching the following criteria are eligible for inclusion into the clinical trial: Inclusion criteria: • Age equal to or greater than 18 years • Curative-intent minimally invasive (robotic-assisted or laparoscopic) liver surgery for confirmed or suspected primary or secondary malignancies Patients are free to withdraw from the study at any time without providing any reason.In general, patients may withdraw from the trial for the following reasons: • At their own request • In the investigator's opinion, if the continuation of the trial is detrimental to the patient's well-being The reason for patient withdrawal will be documented in the (electronic) Case Report Form (eCRF) and in the patient's medical records.

Study termination
Premature termination of the study is at the discretion of the principal investigator and may occur in any of the following events: • Medical or ethical reasons affecting the continuation of the study; • Insufficient patient recruitment.
• External evidence demanding a termination of the trial.
The independent ethics committee has to be informed about termination of the trial Consecutive patients are screened and enrolled, if eligible.Group allocation will be performed via a database randomization tool (REDCap) using block randomization stratified by the difficulty of liver resection and type of malignancy which are deemed to be the most important confounders.Subjects withdrawn from the trial retain their identification codes (e.g.ID number).New subjects receive a new identification code.
Randomization is carried out before the study intervention at visit 1.The details of randomization will be kept safe and confidential.

Performance bias
Treatment of patients follows the German S3-guidelines and the standardized clinical pathways of the Department of Surgery, University Medical Center Mannheim.We expect random occurrence of primary and secondary liver malignancies during recruitment, and we expect random occurrence of variable difficult cases.

Detection bias
Blinding of patients and study stuff is not feasible due to the technical differences between the study intervention.

Reporting and publication bias
The trial will be registered in a registry fulfilling ICMJE criteria.The results will be published in an international journal according to the CONSORT Statement.

3) No need for intravenous fluids 4 )
Independence in mobility or equal to the preoperative levelThe following outcomes will be additionally recorded: a) Time to pain control with oral medication [days]; b) Time to food intake [days]: sips of water, semi-fluid diet, soft bland diet; c) Time to bowel movement [days]: first flatus, first bowel movement; Version 1.0 November 8, 2021 page 11 of 38 d) Time to relief of intravenous fluids [days]; Cardiovascular complications: Myocardial infarction (necrosis of the myocardium due to an interruption of blood supply), Stroke (decrease or absence of blood supply to the brain caused by obstruction (thrombosis or embolism) of an artery resulting in neurological damage), Deep venous thrombosis (formation of a blood clot in large veins) Pulmonary complications: Pulmonary infection 23 , Atelectasis 24 , Acute Respiratory Distress Syndrome 25 , Pulmonary embolism (characterized by occlusion of the pulmonary vessels by a thrombus that has migrated from a distal site via the blood stream)

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Surgical site infection according to the Centers for Disease Control and Prevention grading: superficial, deep, organ/space Intraabdominal fluid collection/abscess: Intraabdominal fluid collection detected on any imaging modality (e.g.ultrasound, CT scan) associated with abdominal discomfort/pain and/or elevation of infectious parameters.Posthepatectomy complications (Grade A-C) according to the International Study Group of Liver Surgery 9,10,28 : Posthepatectomy hemorrhage, Postoperative biliary leakage, Posthepatectomy liver failure.
care will be standardized and kept identical except for the approach of surgery in the study groups (laparoscopic vs. robotic-assisted liver resection).Patients are treated in line with the German S3 guidelines and established clinical pathways of the Department of Surgery, University Medical Center Mannheim.The clinical pathways are outlined as "Standard Operating Procedures" in the document database "roxtra" of the Department of Surgery.Standardization of anesthesiological carePatients are equipped with 16 or 18 Gauge peripheral venous catheter or central venous catheter depending on individual patient´s comorbidities.Patients are treated with general anesthesia receiving antibiotic prophylaxis (2g cefuroxime and 500mg metronidazole, or clindamycin 600mg in case of allergy against cefuroxime respectively gentamicin 3mg/kg body weight in case of allergy against metronidazole) within 30-60 minutes prior to incision.General anesthesia is induced using Thiopental (3-5mg/kg body weight) or Propofol (1-2mg/kg body weight), additional Sufentanil (0.2-0.4mg/kg body weight) and Cisatracurium (0.15mg/kg body weight) or Rocuronium (0.6mg/kg body weight).Anesthesia is maintained using either Sevoflurane (minimal alveolar concentration 0.8) or Desflurane (minimal alveolar concentration 0.8) and additional Sufentanil (up to 1µg/kg body weight total).All drugs are administered adapted to the patient´s body weight.Patients are equipped with gastric tube, arterial catheterization, 16 Gauge peripheral venous catheter, twin lumen central venous catheter (7 French; 18/14 Gauge) or shock catheter (12 French; 12/16/18 Gauge), and transurethral (or suprapubic if contraindicated) catheter with temperature probe, respectively.Intravenous fluid therapy and administration of blood prodcuts will be performed according to local standards aiming a central venous pressure (CVP) below 5mmHg.43 Standardization of postoperative carePatients are transferred either to the post-anesthesia care unit and regular surgical ward, or directly to the intermediate-care unit/intensive-care unit depending on patient´s comorbidities as well as the intraoperative course.In both treatment arms, the postoperative care is identical adhering to enhanced recovery after surgery principles as outlined in the clinical pathways of the Department of Surgery.

38 8 CRITERIA FOR PATIENT WITHDRAWAL AND STUDY TERMINATION 8.1 Patient withdrawal
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